The Long Path to Our Current Understanding Regarding Care of Children with Differences/Disorders of Sexual Development

The term “differences in sex development” (DSD) refers to situations in which sex determination, differentiation of gonads, and development of the internal and external genital structures diverge from characteristic binary male and female development. The process of sex development involves complex sequential signaling networks involving multiple interacting molecular signals, hormonal influences, and cross-talk between these signaling pathways.

Society’s expectation regarding binary sex complicates care for individuals with DSDs and their families. Individuals and families encountering a diagnosis of a DSD are often anxious and apprehensive regarding this sensitive subject. Some individuals present in the neonatal period with atypical genital appearance, whereas others present in childhood with virilization or in adolescence with delayed puberty. We review selected details of the history of this field, recognizing that past and current approaches to medical management adapted contemporary theories regarding sex development to the practice of medicine [1]. Comprehensive reviews regarding the details of sex development, differential diagnosis, and support for patients are available elsewhere [2, 3].

The term “sex” refers to the biological features of an individual. Briefly, females are characterized by XX sex chromosome constitution, development of ovaries and uterus, and ovarian estrogen secretion with onset of puberty. Males are characterized by the presence of a Y chromosome, development of testes, testicular testosterone with puberty, and development of sperm. Physical examination and laboratory studies including gonadal histology have been used to specify sex. Prospective parents anxiously await the pronouncement of their infant’s sex which is proclaimed by prenatal genetic testing, ultrasound examination, or the infant’s birth.

Gender designates a psychosocial concept [4]. The term “gender identity” indicates an individual’s self-perception as female, male, nonbinary, or agender. Gender expression and gender role describe preferences regarding clothing choices, preferred activities, and occupations. Sexual orientation signifies romantic and erotic preferences [5]. Usually, the appearance of the external genitalia, chromosomal constitution, hormone concentrations, gonadal histology, and gender identity are congruent.

Humanity’s curiosity about sex differences has existed for eons – preceding the ability to conduct rigorous scientific inquiry. Ancient creation stories explained the origins of binary sex. The Sumerian creation myth of Enki and Nimnah recorded on clay tablets from 4000–5000 BC described an individual lacking male and female organs [6]. Ishtar, the Babylonian goddess, was represented as a bearded individual dressed in masculine clothing in her role as a goddess of war. Adam and Eve are prominent figures in the early Judeo-Christian traditions. In Plato’s Symposium (c. 385–370 BC), Aristophanes described primeval people (primordial hermaphrodites) as spherical creatures with four hands, four legs, and two faces gazing in opposite directions. The Greek gods, especially Zeus, were terrified by the power of these creatures and split them into halves creating two sexes and doubling their number of worshippers. Apollo closed the wound leaving the umbilicus as a reminder of humankind’s origins. The two halves, as originally created by Zeus, perished due to hunger in their desperate search to reconnect for love. Zeus took pity on them and moved their genitalia to the front inventing internal reproduction – by the man into the woman. Consequently, Aristophanes claimed that the origin of Love was biological [7, 8]. The Talmud discusses that legal and practice issues occurred because hermaphrodites could not be ascribed to one sex [9].

Ancient Greek philosophers debated binary sex determination including the origin of infants with atypical genitalia. As described by Mittwoch, ancient Greek philosophers debated binary sex determination including the origin of infants with atypical genitalia [3, 10, 11]. Parmenides (c. 515–460 BC) hypothesized that sex was determined by the position of the fetus in the uterus, whereas Anaxagoras (c. 500–428 BC) suggested that semen from the right testis created a male and semen from the left testis created a female [3, 10, 11]. Aristotle countered these notions with a temperature hypothesis in which males were warm and females were cold. Physical development of the body could be ambiguous, but sex (and gender roles) needed to be binary.

Between the 2nd to 16th centuries, human anatomical studies were rarely performed due to the prohibitions against dissection, limited availability of human corpses, and the need to pay for them [12]. Indeed, Galen’s writings regarding anatomy primarily reflected his comparative animal dissections [13]. In the 1550s, Gabriele Falloppio, an Italian priest and anatomist, described the internal reproductive structures in both men and women including similarities between the penis and the clitoris [14-16]. Falloppio did not hesitate to expose incorrect anatomic reports leading to public correspondence with another prominent anatomist, Andreas Vesalius [17], who authored the first illustrated anatomy textbook De Humani Corporis Fabrica in 1543 [18]. In 1651, William Harvey (1578–1657) published his book stating that all animals are “engendered from an egg,” challenging the theories about the roles of temperature and sidedness in embryology [19, 20].

Melchisedec Thévenot (c. 1620–1692), a French patron of the sciences, and his students, Jan Swammerdam (1637–1680) and Niels Stenson (“Steno”) (1638–1686), investigated reproduction and comparative anatomy. Despite the lack of conclusive evidence, Steno predicted that ovaries contained eggs [21]. Swammerdam then collaborated with Johannes Van Horne in Leiden in 1668 [22]. Swammerdam learned that he was competing with a former student and colleague, Regnier de Graaf (1641–1673), a Dutch anatomist who was also studying mammalian ovaries. In 1671, de Graaf hastily published his hypothesis about how eggs in the “female testicle” became fertile [23]. In 1672, de Graaf won the scholarly race by publishing his De Mulierum Organis Generationi Inservientibus Tractatus Novus (“New treatise concerning the generative organs of women”) in which he described small vesicles full of liquid which he considered to be eggs [24]. Despite the publication of de Graaf’s work, Swammerdam and de Graaf continued their quarrelsome correspondence regarding who first discovered “eggs” [25, 26]. However, the final outcome was the acceptance of the concept that all animals developed from eggs. In retrospect, the structures observed by de Graaf were actually follicles and not oocytes (hence the term “Graafian follicles”) [27]. In addition to describing ovarian follicles, de Graaf published on male and female internal genital structures.

de Graaf provided additional details regarding the male reproductive system in 1668 and the female system in 1672 [28, 29]. Caspar Friedrich Wolff described the Wolffian duct system in 1759 [30]. Wolff also suggested that development of an organism involved successive stages, which ran counter to the prevailing view that sperm contained preformed humans. Approximately 70 years later in 1827, Karl Ernst von Baer described the human egg within the Graafian follicle [31]. Johannes Peter Müller, a German physiologist and comparative anatomist, described the Müllerian ducts in 1830 [32].

Using his hand-crafted microscope, Antonie Van Leeuwenhoek (1632–1723) observed sperm cells thrashing about in human, horse, and dog semen in the 1670s; he labeled these cells as animalcules [33, 34]. Considering the animalcules to be parasites, Von Baer named them spermatozoa [35]. The term “spermatozoa” is derived from Greek and translates to “animal in the seed” or “seed animal” because “sperma” is seed and “zoon” means living thing. In 1841, Rudolph Alfred von Kölliker (1817–1905) concluded that spermatozoa were not true animals. Rather spermatozoa were produced by the testes and needed to come into contact with ova for successful reproduction [36, 37]. German histologist and zoologist Franz Leydig (1821–1908) described individual multinucleated cells forming clusters between seminiferous tubules in 1850 [38, 39].

In 1865, Enrico Sertoli characterized the branched cells that enclose the seminiferous tubules and described spermatozoa within the tubules [40]. Using sea urchins, in 1878, Oscar Hertwig confirmed that reproduction involved a sperm cell entering an egg followed by fusion of the cell nuclei [41]. The existing beliefs that environmental factors such as nutrition and temperature governed human fetal sex determination changed with the development of the hormonal theory of sex differentiation and discovery of chromosomes [42, 43].

Men have historically been associated with power, money, and position. Marriage and fatherhood documented “maleness.” In a few famous cases, physicians examined and adjudicated the social sex for individuals with atypical genitalia in France. Ambroisé Paré (1517–1590) described four types of “hermaphrodites”: (1) fertile male sex with a shallow hole in perineum; (2) female with normal external female external genitalia, menses, and small penis; (3) genital ambiguity and infertility; and (4) two sets of external genitalia [44]. A French physician, Jean Riolan, reported in 1614 that he was not surprised by the presence of “hermaphrodites” in Paris [45, 46]. These cases emphasized the contemporaneous anxieties regarding sexual function, genital anatomy, urination, ejaculation, and gender [47].

European physicians and scientists debated theories for binary sex development. One theory indicated that women’s bodies existed as failed male bodies due to the absence of heat at conception. Another theory stated that the initially neutral fetus was impacted by an external influence to develop as male or female. Robert Knox (1791–1862), Edinburgh anatomist, thought that all fetuses began with both male and female anatomy [48, 49]. In his 1750 publication entitled A Dissertation on Hermaphrodites, George Arnaud de Ronsil, a surgeon in London, reported “that people with unclear sex in Europe visited surgeons to relieve pain or treat cosmetic issues” [50, 51]. By the late 19th and early 20th century, it was generally accepted that “the true sex” was determined by the gonads and that “the true sex” established gender role.

In 1903, Pol Bouin and Paul Ancel first suggested that the internal secretions (later termed “hormones”) of the interstitial testicular cells were responsible for male sex differentiation [52]. Frank Lillie in Chicago, and Keller and Tandler in Austria, provided additional evidence for the hormonal theory of sex development by studying “freemartins.” Freemartins are genetic female products of twin/multiple pregnancies including at least one male; they are typically infertile with stunted ovaries, absent or vestigial Mullerian duct derivatives, and some Wolffian duct elements in the absence of virilization of the external genitalia. Lillie stated that fetal blood carried specific hormones that affected ovarian development [53, 54]. Following his report, Lillie gracefully acknowledged that Karl Keller and Julius Tandler had published about freemartins prior to his publication. Keller and Tandler had identified the shared blood circulation that enabled transfer of hormonal factors [55]. More recent work has shown that Anti-Mullerian Hormone (AMH) rather than testosterone influences ovarian development in freemartins [56].

In the 1940s, Alfred Jost continued the study of hormone effects on sex development. He noted that species-specific critical stages governed aspects of sex development. He performed his pivotal experiments on embryonic rabbits showing that testicular hormones govern internal sex duct and external genital development, concluding that testosterone promoted virilization of the external genitalia and persistence of the Wolffian ducts [57-59]. He introduced the concept that the testis makes two hormones, a masculinizing hormone similar to testosterone and a Mullerian inhibitor hormone. Jost also determined that gonadotropins influenced testicular androgenic activity but not Mullerian inhibitory activity [60]. In the 1960s, Peter Hall and Kristen Eik-Nes confirmed that pituitary gonadotropic hormones stimulated androgen formation by testes [61].

Heinrich Wilhelm Waldeyer observed string-like bodies in cell nuclei in 1888 due to their characteristic staining with certain dyes; he called them chromosomes [62]. In 1902, Clarence Erwin McClung described the role of chromosomes in sex determination and stated that “It is very probable that, in certain species, sex is determined at the time of fertilization and can not be altered by any later influences” [63]. In 1905, Nettie Maria Stevens and Edmund Beecher Wilson independently investigated the hypothesis that chromosomes, specifically the X and Y chromosomes, influence sex determination [64, 65].

By investigating patients with DSDs, the genetic region responsible for testicular differentiation was assigned to the short arm of the Y chromosome. In 1989, Mark Palmer et al. [66] reported four variably masculinized patients with testicular tissue who shared some Y-derived markers including a 35-kb region located at Yp11.2. Conclusive proof that this 35-kb region was the sex-determining region was obtained by the creation of a transgenic sex-reversed XX mouse [67]. Confirmation of the role of the SRY gene in sex determination and development of novel genetic tools inaugurated the discovery and identification of novel genes involved in the process of sex development [68]. Reviews of these discoveries are available [69-71].

Since ancient times, castration was known to cause loss of secondary sexual characteristics [72]. Such knowledge led Arnold Adolph Berthold (1803–1861) to transplant testes from roosters to capons resulting in the restoration of androgen actions; these experiments led to his hypothesis regarding testicular humoral substances [73]. The belief in the importance of testes for male vigor is ancient, as evidenced by Gaius Plinius Secundus (Pliny the Elder) (23–79 AD) who recommended ingestion of animal testes to treat hypogonadism [74, 75]. Testicular organotherapy was popularized when, in 1889, renowned scientist Charles-Edouard Brown-Séquard (1847–1894) reported restored vigor following daily self-injections containing an aqueous slurry of testicular vein blood, semen, and liquid extracted from dog or guinea-pig testes [76]. Brown-Séquard presumably reported a placebo response because insignificant quantities of testosterone are stored in testes and the aqueous slurry was unlikely to solubilize steroids. Nevertheless, his report stimulated future endocrine discovery.

In 1935, Ernst Laqueur (1866–1947) and his colleagues isolated 15 mg of crystalline testosterone from several tons of steer testes [77]. That same year, due to cooperation between academia and industry, Butenandt and Hanisch at the University of Gdansk and Ruzicka and Wettstein in Switzerland published the chemical synthesis of testosterone [78, 79]. These publications initiated the steroid pharmacologic industry and opened the door to investigation of reproductive physiology.

In 1937, Pettersson and Bonnier described a family in which three phenotypic females with primary amenorrhea presented with inguinal masses; all three had blind vaginal pouches, absence of internal female genital structures, and testes [80]. These cases are presumed to represent individuals with complete androgen insensitivity (CAIS). The terminology “testicular feminization” was introduced by Morris and Mahesh in 1953 [81]. When visiting Lawson Wilkins in 1949, Jost suggested that although these patients were insensitive to androgens, they retained normal production and sensitivity to the Müllerian inhibitor [82, 83]. In 1957, Wilkins showed that a patient with “testicular feminization” failed to respond to methyltestosterone [84]. Subsequently, Barbara Migeon et al. [85] mapped the human androgen receptor locus to the X chromosome near the centromere. In their review of the defective cytosolic androgen receptor activity in rodent models of androgen insensitivity, Bardin and Bullock predicted that genetic changes in the androgen receptor gene would be identified in individuals with androgen insensitivity [86]. Subsequently, Lubahn et al. [87] identified a point mutation in the androgen receptor gene in a family with complete androgen insensitivity syndrome. Extensive phenotypic and genetic heterogeneity occurs among individuals with androgen insensitivity ranging from complete to partial forms [88, 89].

With elucidation of steroid biosynthetic pathways, prismatic reports substantiated the importance of C19 steroid (androgen) biosynthesis and action for male sex development [90, 91]. An early description of what may have been 5α-reductase or 17β-hydroxysteroid dehydrogenase deficiency involved the story of Herais around 145 BC in Arabia. Herais was raised as a girl and married at a young age. While her husband was on a long journey, she developed severe abdominal pain with sudden appearance of testes and a penis. Herais changed gender to male and later fought in the king’s army [92].

In 1961, Nowakowski and Lenz described 46,XY individuals in whom androgen concentrations and testes were male, external genitalia were female, and the Wolffian ducts terminated in a blind-ending vagina [93]. Subsequent investigation by Jean Wilson and colleagues demonstrated autosomal recessive inheritance and association with 5α-reductase deficiency [94]. Andersson et al. [95] confirmed that SRD5A2 mutations were associated with 5α-reductase deficiency. In 1974, Imperato-McGinley et al. [96] described individuals in the Dominican Republic with pseudovaginal perineoscrotal hypospadias, microphallus, and undescended testes who virilized with the onset of puberty. Affected individuals were initially raised as girls and typically transitioned to male gender during puberty. These boys, who had been raised as girls, developed testes and a penis at age 12 years, and subsequently stopped performing female household chores, were labeled as “guevedoces,” which refers to “penis at 12.” Thigpen et al. [97] later identified mutations in the 5α-reductase type 2 (SRD5A2) gene in affected individuals.

In 1965, Neher and Khant [98] reported a patient with atypical genital development associated with deficiency of 17β-hydroxysteroid dehydrogenase (17β-HSD, also known as 17-ketosteroid reductase). Additional reports soon followed, including the description of an extended inbred Arab family in Israel [99]. Imperato-McGinley et al. [100] reported an individual with 17β-HSD deficiency who was reared as a girl, virilized during puberty, and successfully transitioned to male gender identity when 14 years old. It is now known that there are as many as 12 different 17β-HSDs, but the isozyme involved in these DSD patients is the “type 3” enzyme (HSD17B3), which is abundantly expressed in the testis and is the principal enzyme that converts androstenedione to testosterone [101, 102].

Some genetic disorders compromise steroidogenesis in both adrenal cortex and gonads. Biglieri et al. [103] reported a 35-year-old woman who had delayed puberty, hypertension, and hormone concentrations suggestive of decreased 17α-hydroxylase deficiency. Between 1981 and 1984, Peter Hall had shown that the purified bovine and pig adrenal P450c17 catalyzed both 17α-hydroxylase and the 17,20-lyase activities [104]. Finding mutations in the CYP17A1 gene in a patient substantiated that one protein was responsible for this disorder [105]. Congenital lipoid adrenal hyperplasia is an autosomal recessive disorder associated with sex steroid, glucocorticoid, and mineralocorticoid deficiencies. Walter Miller, Jerome Strauss, and colleagues solved the puzzle of the molecular genetics of this disorder in 1995 when they identified mutations in the steroidogenic acute regulatory protein (StAR) gene [106, 107]. In 2005, Miller and colleagues reported the association of Antley-Bixler syndrome, atypical external genital development, and mutations in the P450 oxidoreductase deficiency [108]. Other studies showed that both the conventional pathway of testosterone synthesis and the newly discovered “backdoor pathway” participate in testicular androgen biosynthesis [109, 110].

In 1935, Lawson Wilkins, one of the founding fathers of pediatric endocrinology, was appointed to the directorship of the Pediatric Endocrine Clinic by Dr. Edwards Park. Wilkins established the world’s first pediatric endocrine clinic at the Johns Hopkins Hospital. In 1950, both Wilkins and Frederic Bartter and Fuller Albright reported successful treatment of 21-hydroxylase deficiency with cortisone; Bartter and Albright proposed that the “adrenogenital syndrome results, not from an abnormal pituitary stimulation of the adrenal, but from an abnormal adrenal response to a normal pituitary” [111]. Subsequently, in 1951, Wilkins, and Bartter and Albright, independently and simultaneously described the efficacy of cortisone in preventing the progressive postnatal virilization of girls with classical congenital adrenal hyperplasia (CAH). The history of CAH is detailed by Miller and White [112].

In 1955, Wilkins and his team of associates published “Hermaphroditism: Classification, Diagnosis, Selection of Sex and Treatment” in Pediatrics [113]. The authors proposed a classification system based on Jost’s findings regarding embryonic development and utilized this classification system to guide medical interventions and sex assignment. Based on physical examination and laboratory studies, individuals were slotted into specific categories. Although the term “hermaphrodite” has now been eliminated from usage and the genetic vocabulary has expanded, this cataloging system provides some structure to our current approach to the patient with DSD [114].

Wilkins and colleagues espoused that a child’s lived experiences, as a boy or a girl, established an individual’s gender role and erotic orientation. Wilkins based this notion on the work of Dr. John Money who had joined the team in 1951 [115]. Money, a psychologist, was a pioneer investigator regarding hermaphroditism and gender identity. Working with John Hampton and Joan Hampton, Money proposed that one’s psychosexual development was determined not by any single factor but through the interactions between biological and social factors. They contended that the gender of rearing was an important factor because gender identity and role were learned and established through the accumulation of lived experiences. Thus, Money’s hypothesis assumed that gender identity was not firmly established at birth, reflected the outcome of multiple pre- and postnatal factors, and was primarily dominated by “assigned gender role.” In other words, nurture prevailed over nature. Money and colleagues conjectured that successful psychological outcome for individuals with atypical genitalia depended on the congruence of the physical body and gender role.

During the early years of pediatric endocrinology in the 1950s, the prevailing philosophy was that the birth of a child with atypical external genitalia was a social emergency. Parents were advised to share their child’s situation only with family members. The Hopkins team recommended sex/gender assignment based on the appearance of the external genital structures, particularly the size of the phallus and the presence of an adequately sized vagina regardless of chromosome patterns, gonad, or internal genital structures. Based on this philosophy, infants with an undersized phallus, the absence of a phallus, or female appearing external genital structures were assigned to female sex of rearing [116]. One exception was that girls with atypical genitalia due to CAH should be raised as girls. Virilized females with CAH were treated by surgical procedures to make the external genital appear more female [117].

Upon Wilkins’ retirement, Drs. Robert Blizzard and Claude Migeon became co-directors of the Johns Hopkins Pediatric Endocrinology Clinic. They initially continued to utilize the “optimal gender” approach congruent with capacity for traditional sexual intercourse, potential for fertility, and assumptions regarding future quality of life. This approach, based on Money’s hypotheses, assumed that gender identity was not established at birth, reflected the outcome of multiple pre- and postnatal factors, and was primarily dominated by “assigned gender role.” However, several challenges surfaced regarding this hypothesis resulting in changes in approaches to care.

One challenge involved reports of 46,XY individuals born with cloacal exstrophy who were assigned to female sex of rearing at birth; over time, some of these individuals developed male gender identities [118-120]. A second challenge arose from the popularized report of the John-Joan case in which a 46,XY twin boy suffered the traumatic loss of his penis during a circumcision at 8 months of age. The family consulted with Money when this child was 17 months of age. Money indicated that female gender reassignment would be the best option based on his hypothesis that the gender of rearing was the predominant factor governing gender identity. Reassignment was followed by surgery at 22 months to feminize the appearance of the external genitalia. Despite Money’s initial optimistic reports, the patient self-identified as male and re-assigned to male at 14 years of age. The third challenge were the reports of transition of 46,XY individuals with either 17β-hydroxysteroid dehydrogenase type 3 or 5α-reductase type 2 deficiency to male gender roles during puberty [88, 92, 95, 97]. While these situations were unfolding, Peter Lee and colleagues published guidelines for penile measurement and data regarding stretched penile length in normal males [121].

In 1993, an affected individual founded the Intersex Society of North America (ISNA) to share the stories of individuals with atypical genitalia and to advocate for more thoughtful inclusive care. ISNA transitioned to Interact/Advocates for Intersex Youth in 2008 [122]. These and other patient-physician dialogues, including an international consensus conference, led to the development of a multidisciplinary team approach involving multiple healthcare professionals and implementation of shared decision-making [123-125].

In 2012, Jean Wilson, Marco Rivarola, Berenice Mendonca, Garry Warne, Nathalie Josso, Stenvert L.S. Drop, and Melvin Grumbach provided advice for young endocrinologists when faced with a patient with a DSD. This joint publication contains “pearls of wisdom” relevant today supplementing the current knowledge regarding the molecular genetics of sex development. Specific recommendations include “do not guess,” utilize a team approach, involve and educate the parents, consider the parents’ level of understanding, cultural expectations, and religious beliefs, and accept uncertainty [126, 127].

Diodorus Siculus (ca. 80–20 BC) provided one of the earliest descriptions of genital surgery involving a person named Callo who had been raised as a female and developed a painful swelling in the genital region. Upon cutting into this swollen area, male genitalia appeared and Callo “transitioned” from female to male. Most likely, Callo had 17β-HSD or 5α-reductase deficiency [128, 129]. Şerafeddin Sabuncuoğlu, a 15th century surgeon in Anatolia, wrote a three-volume pediatric surgical atlas “Cerrahiye-i Ilhaniye” in which he discussed the surgical treatment of various genital anomalies [130, 131].

In the 1930s, steroid biochemistry progressed. At the First International Conference on the Standardization of Sex Hormones held in London in 1932, Edmund Doisy, Adolf Butenandt, and Guy Marrian concurred that steroids were composed of four rings and that the fourth ring had five carbon atoms [132]. One of the next steps was the ability to measure steroid hormones. Based on the growth response of a cock’s comb to transplanted testes, C.R. Moore and colleagues established a bioassay to measure androgenic activity [133]. Bioassays were confounded by technical complexity and poor reproducibility [134]. Immunoassays for sex steroids followed, but they typically required laborious and expensive steps of solvent extraction and chromatography to increase the sensitivity and specificity of the immunoassay, and generating antibodies specific against small steroid molecules was difficult [135]. More sensitive and specific mass spectrometric methods for measuring steroid hormones in blood and urine have now been developed [136-138].

A consensus conference was organized in response to the recognition that care of those with DSDs needed to be evaluated. Factors involved included the lack of patient and family involvement in medical decisions, nondisclosure of findings, repeated and nonprivate medical examinations, questions regarding impact of fetal androgen levels, and the option of deferring surgery [139].

In 2005, a Consensus Conference addressed issues that required more information, including gender, gender identity, and surgery. This was not a set of clinical guidelines, and additional details, especially outcome data, were needed before guidelines could be developed. The currently advocated medical approach emphasizes awareness and openness to diversity, recognizing the importance of individual choices regarding gender identity, and will likely improve outcomes for individuals with DSD [140]. This involves a team approach, a de-emphasis of repeated physical examinations (after an initial complete examination), greater accuracy of hormone and genetic testing, and full disclosure including discussion of information found in the social media and from support groups [141]. Genital surgery for mild to moderate virilization among 46,XX patients may be omitted or delayed, but it remains very controversial when the genitalia differ from the sex of rearing.

More than 50 years ago, the first systematic approach for diagnosing and treating intersexuality was proposed [113]. The Hopkins group developed the first multidisciplinary team to provide what was considered best standard of care at the time. Over time, major changes in philosophy and healthcare approach have occurred, particularly regarding surgery and because of the uncertainty of gender development. Currently, centers of excellence with multidisciplinary teams exist in the United States including those that are part of the DSD-Translational Network (DSD-TRN) website, and centers in Europe [142]. Centers are attuned to new outcome evidence, shifting social (including electronic media) pressures, and most importantly each individual situation. Despite the best intentions of parents and the DSD teams, gender assignment remains an imperfect art. Medical and mental health professions should continue to support the mental health needs of this population so that the potential for the best life possible, envisioned by Dr. Wilkins, can become a reality.

The authors Selma F. Witchel, Tom Mazur, Christopher P. Houk, and Peter A. Lee declare no conflict of interest. Selma F. Witchel is granted sponsored research support from Neurocrine Pharmaceuticals.

Selma F. Witchel, Tom Mazur, Christopher P. Houk, and Peter A. Lee received no funding for this review.

Selma F. Witchel and Peter A. Lee conceived the project. Tom Mazur and Christopher P. Houk contributed to the writing of the report and approved multiple versions.